The overall goal of the proposed research is to investigate the mechanisms of allogeneic stem cell education inpatients with severe combined immunodeficiency (SCID) given non-ablated transplants of rigorously T cell-depleted related bone marrow cells. The investigator has administered the latter therapy to 134 such infants at Duke over the past 21.8 years, with an overall survival rate of 77%. However, the immune reconstitution in these patients is not perfect. The Aims of the proposed research are to discover the reasons for the less than optimal immune reconstitution. Aim 1) To characterize the phenotypes and functions of T cells longitudinally after allogeneic stem cell therapy in infants with SCID. Thymic output will be monitored by TRECs and T cell diversity by Immunoscope analyses. The hypotheses to be tested are: 1) that the decreased thymic output in later years is due to the fact that the stem cells and the thymus are haploidentical to each other, 2) that this is not due to an intrinsic inability of the SCID thymus to maintain thymic output beyond the first decade of life, and 3) that the absence in SCIDs of normal sized peripheral lymphoid tissues, necessary to maintain T cell homeostasis, may affect the T cell repertoire diversity as well as the types of cytokines they produce. Aim 2) To examine why some patients engraft donor B cells and others do not and to discover why host B cells in certain types of SCID produce immunoglobulins normally while others do not. The hypotheses to be tested are: 1) that GVHD facilitates donor B cell engraftment, 2) that this is contributed to by transplacental transfer of maternal lymphocytes while the infant is in utero, 3) that NK cell development prior to T cell development has no effect on the development of B cell function, 4) that the underlying mutation determines the ability of the host B cell to function, and 5) that the lack of development of FDC networks, germinal centers, class switch, and antibody response may be related to altered LT expression and/or function. Aim 3) To examine whether host dendritic cell abnormalities contribute to inadequate B and NK cell functions in X-linked and Jak3-deficient SCIDs. The hypothesis to be tested is that the host dendritic cells cannot function due to defects caused by the underlying mutations in these types of SCID and that donor-derived NK cells and functions will decline with time due to abnormal IL-15-dependent host dendritic cell (DC) functions. The function of blood monocyte-derived DC will be assessed by measuring DC IL-12 release (following stimulation with LPS, anti-CD40 and cytokines) and DC capacity to activate allogeneic T cells.